Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome
Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome
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DOI：
10.1016/j.jaci.2011.03.030
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发表时间：
2011-06-01
影响因子：
14.2
通讯作者：
Villa, Anna
中科院分区：
文献类型：
--
作者：
Bosticardo, Marita;Draghici, Elena;Villa, Anna
背景资料：Wiskott-Aldrich综合征（WAS）是一种X连锁原发性免疫缺陷，其特征为血小板减少症、湿疹、感染、自身免疫和淋巴瘤。从HLA相合的供者移植造血干细胞是有疗效的，但并非所有患者都能获得。我们已经开发了一种基因治疗（GT）的方法，通过使用慢病毒载体编码的人WAS启动子/cDNA目的：评价GT处理小鼠的B细胞重建和B细胞表型的纠正。方法：我们移植了亚致死剂量照射的Was（-/-）小鼠（700拉德）与谱系标志物耗尽的骨髓野生型细胞，Was（-/-）细胞未转导或用w1.6W慢病毒载体转导，并分析骨髓中的B细胞重建，结果：WAS蛋白（+）B细胞存在于经GT处理的小鼠的中央和外周B细胞区室中，并且在脾边缘区和腹膜B1细胞亚群中显示出最强的选择性优势。GT后，脾结构得到改善，B细胞功能得到恢复，所证明的肺炎球菌抗原的抗体反应和血清IgG自身antibodies.Conclusion：WAS GT导致B细胞功能的改善，即使在存在混合嵌合体，进一步验证了w1.6W慢病毒载体的临床应用。（J Allergy Clin Immunol 2011;127：1376-84.）
Background: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, eczema, infections, autoimmunity, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical donors is curative, but it is not available to all patients. We have developed a gene therapy (GT) approach for WAS by using a lentiviral vector encoding for human WAS promoter/cDNA (w1.6W) and demonstrated its preclinical efficacy and safety.Objective: To evaluate B-cell reconstitution and correction of B-cell phenotype in GT-treated mice.Methods: We transplanted Was(-/-) mice sublethally irradiated (700 rads) with lineage marker-depleted bone marrow wild-type cells, Was(-/-) cells untransduced or transduced with the w1.6W lentiviral vector and analyzed B-cell reconstitution in bone marrow, spleen, and peritoneum.Results: Here we show that WAS protein(+) B cells were present in central and peripheral B-cell compartments from GT-treated mice and displayed the strongest selective advantage in the splenic marginal zone and peritoneal B1 cell subsets. After GT, splenic architecture was improved and B-cell functions were restored, as demonstrated by the improved antibody response to pneumococcal antigens and the reduction of serum IgG autoantibodies.Conclusion: WAS GT leads to improvement of B-cell functions, even in the presence of a mixed chimerism, further validating the clinical application of the w1.6W lentiviral vector. (J Allergy Clin Immunol 2011;127:1376-84.)